DESCRIPTION (Verbatim from the applicant?s abstract) The research objective of this application is to further our understanding of local anesthetics and voltage-gated sodium channel pharmacology by using calcium channel blockers as unique molecular probes. The study begins with a detailed evaluation of sodium channel affinities for calcium channel blockers in comparison with known local anesthetics. Preliminary data indicate that calcium channel blockers may bind to known local anesthetic sites, and some of these agents block sodium current more potently than common local anesthetics such as bupivacaine. Prenylamine, a calcium channel blocker, at 31.LM is an effective use-dependent blocker of human cardiac sodium channels during repetitive pulses. There is significant tonic block for resting and for inactivated hill channels by the calcium channel blockers. Furthermore, in vivo data from rats injected at the sciatic nerve site with prenylamine suggest that some calcium channel blockers may have longer nociceptive, proprioceptive, and motor block than the long-acting local anesthetics, such as bupivacaine, used today in the clinics. Thus, the experiments outlined for AIM1 will determine the resting/ inactivated affinities of neuronal and cardiac sodium channels as well as mapping out the receptor sites on these channels for the calcium channel blockers. Experiments in AIM2 are designed to evaluate the possible clinical benefits of calcium channel blockers in vivo on rat sciatic nerves.